AR035957A1 - PROCEDURE FOR THE PREPARATION OF 1,3-SUBSTITUTES AND AZAPOLICICLIC COMPOUNDS CONDENSED WITH ARILOS - Google Patents

PROCEDURE FOR THE PREPARATION OF 1,3-SUBSTITUTES AND AZAPOLICICLIC COMPOUNDS CONDENSED WITH ARILOS

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AR035957A1
AR035957A1 ARP020101424A ARP020101424A AR035957A1 AR 035957 A1 AR035957 A1 AR 035957A1 AR P020101424 A ARP020101424 A AR P020101424A AR P020101424 A ARP020101424 A AR P020101424A AR 035957 A1 AR035957 A1 AR 035957A1
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alkyl
alkoxy
fluorine
carbon atoms
aryl
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Spanish (es)
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Pfizer Prod Inc
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    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane

Abstract

Procedimiento para la preparación de cualquiera de los indenos 1,3-sustituidos intermedios de las fórmulas (1), (2) y (3) o una mezcla de los mismos, en donde R2 y R3 se seleccionan, independientemente, entre hidrógeno, flúor, cloro, -SOq-alquilo C1-6, siendo q cero, uno o dos, (alquil C1-6)2-amino, -CO2R7, -CONR8R9, -SO2NR10R11, aril-alquil(C0-3)- ó aril-alquil(C0-3)-O-, seleccionándose dicho arilo entre fenilo y naftilo, heteroaril-alquil(C0-3)- ó heteroaril-alquil(C0-3)-O-, seleccionándose dicho heteroarilo entre anillos aromáticos de cinco a siete miembros que contienen de uno a cuatro heteroátomos seleccionados entre oxígeno, nitrógeno y azufre; X2-alquil(C0-6)- y X2-alcoxi(C1-6)-alquil(C0-6)-, estando X2 ausente o siendo X2 alquil(C1-6)-amino- ó (alquil(C1-6))2-amino y conteniendo los restos alquil(C0-6)- ó alcoxi(C1-6)-alquil(C0-6)- de dichos X2-alquil(C0-6)- ó X2-alcoxi(C1-6)-alquil(C0-6)- al menos un átomo de carbono y pudiendo reemplazarse opcionalmente de uno a tres de los átomos de carbono de dichos restos alquil(C0-6)- ó alcoxi(C1-6)-alquil(C0-6)- por un átomo de oxígeno, nitrógeno o azufre, con la condición de que dos cualesquiera de dichos heteroátomos deben estar separados por al menos dos átomos de carbono y pudiendo estar cualquiera de los restos alquilo de dichos grupos alquil(C0-6)- ó alcoxi(C1-6)-alquil(C0-6)- opcionalmente sustituido con dos a siete átomos de flúor y pudiendo reemplazarse opcionalmente uno de los átomos de carbono de cada uno de los restos alquilo de dicho aril-alquil(C0-3)- y dicho heteroaril-alquil(C0-3)- por un átomo de oxígeno, nitrógeno o azufre, y pudiendo estar opcionalmente sustituido cada uno de los grupos arilo y heteroarilo anteriores con uno o más sustituyentes, preferiblemente de cero a dos sustituyentes, seleccionados independientemente entre alquilo C1-6 opcionalmente sustituido con uno a siete átomos de flúor, alcoxi C1-6 opcionalmente sustituido con dos a siete átomos de flúor, cloro, flúor, (alquil(C1-6))2-amino-, -CO2R7, -CONR8R9 y -SO2NR10R11; ó R2 y R3, junto con los carbonos a los que están unidos, forman un anillo carbocíclico monocíclico de cuatro a siete miembros, o bicíclico de diez a catorce miembros, que puede estar saturado o insaturado, pudiendo reemplazarse opcional e independientemente de uno a tres de los átomos de carbono no condensados de dichos anillos monocíclicos y de uno a cinco de los átomos de carbono de dichos anillos bicíclicos que no forman parte del anillo de benceno mostrado en la fórmula (4), por un nitrógeno, oxígeno o azufre y pudiendo estar opcionalmente sustituidos dichos anillos monocíclicos y bicíclicos con uno o más sustituyentes, preferiblemente de cero a dos sustituyentes para los anillos monocíclicos y de cero a tres sustituyentes para los anillos bicíclicos, que se seleccionan, independientemente, entre alquil(C0-6)- ó alcoxi(C1-6)-alquil(C0-6)-, sin que el número total de átomos de carbono exceda de seis y pudiendo estar opcionalmente sustituido cualquiera de los restos alquilo con uno a siete átomos de flúor; oxo, flúor, cloro, (alquil C1-6)2-amino-, -CO2R7, -CONR8R9 y -SO2NR10R11; cada uno de R7, R8, R9, R10 y R11 se selecciona, independientemente, entre hidrógeno y alquilo C1-6, ó R8 y R9, ó R10 y R11, junto con el nitrógeno al que están unidos, forman un anillo de pirrolidina, piperidina, morfolina, azetidina, piperazina, -N-alquil(C1-6)-piperazina o tiomorfolina, o un anillo de tiomorfolina en el que el azufre del anillo se reemplaza por un sulfóxido o sulfona; y cada X es, independientemente, alquileno C1-6; R5 es alquilo C1-6 o Si(R12)3; R1 es un grupo de extracción de electrones seleccionado entre ciano, alcoxicarbonilo, alquilcarbonilo, arilcarbonilo, arilo, nitro, trifluorometilo y sulfonilo; cada R4 es independientemente H, alquilo C1-6, H(L)3N+, o un catión metálico, incluyendo cationes de metales alcalinos de Na, K, Li o Cs; o dos grupos R11 conjuntamente forman un enlace alquileno C2-3; cada L es independientemente H, alquilo C1-6, fenilo o bencilo; y cada R12 es independientemente alquilo C1-6 o fenilo. Los compuestos de fórmulas (1), (2) y (3), o las mezclas de los mismos, son útiles en la preparación de compuestos de fórmula (4) en la que R6 es hidrógeno; en la que R2 y R3 se seleccionan, independientemente, entre hidrógeno, flúor, cloro, -SOq-alquilo C1-6, siendo q cero, uno o dos, (alquil C1-6)2-amino, -CO2R7, -CONR8R9, -SO2NR10R11, aril-alquil(C0-3)- ó aril-alquil(C0-3)-O-, seleccionándose dicho arilo entre fenilo y naftilo, heteroaril-alquil(C0-3)- ó heteroaril-alquil(C0-3)-O-, seleccionándose dicho heteroarilo entre anillos aromáticos de cinco a siete miembros que contienen de uno a cuatro heteroátomos seleccionados entre oxígeno, nitrógeno y azufre; X2-alquil(C0-6)- y X2-alcoxi(C1-6)-alquil(C0-6)-, estando X2 ausente o siendo X2 alquil(C1-6)-amino- ó (alquil(C1-6))2-amino y conteniendo los restos alquil(C0-6)- ó alcoxi(C1-6)-alquil(C0-6)- de dichos X2-alquil(C0-6)- ó X2-alcoxi(C1-6)-alquil(C0-6)- al menos un átomo de carbono y pudiendo reemplazarse opcionalmente de uno a tres de los átomos de carbono de dichos restos alquil(C0-6)- ó alcoxi(C1-6)-alquil(C0-6)- por un átomo de oxígeno, nitrógeno o azufre, con la condición de que dos cualesquiera de dichos heteroátomos deben estar separados por al menos dos átomos de carbono y pudiendo estar cualquiera de los restos alquilo de dichos grupos alquil(C0-6)- ó alcoxi(C1-6)-alquil(C0-6)- opcionalmente sustituido con dos a siete átomos de flúor y pudiendo reemplazarse opcionalmente uno de los átomos de carbono de cada uno de los restos alquilo de dicho aril-alquil(C0-3)- y dicho heteroaril-alquil(C0-3)- por un átomo de oxígeno, nitrógeno o azufre, y pudiendo estar opcionalmente sustituido cada uno de los grupos arilo y heteroarilo anteriores con uno o más sustituyentes, preferiblemente de cero a dos sustituyentes, seleccionados independientemente entre alquilo C1-6 opcionalmente sustituido con uno a siete átomos de flúor, alcoxi C1-6 opcionalmente sustituido con dos a siete átomos de flúor, cloro, flúor, (alquil(C1-6))2-amino-, -CO2R7, -CONR8R9 y -SO2NR10R11; ó R2 y R3, junto con los carbonos a los que están unidos, forman un anillo carbocíclico monocíclico de cuatro a siete miembros, o bicíclico de diez a catorce miembros, que puede estar saturado o insaturado, pudiendo reemplazarse opcional e independientemente de uno a tres de los átomos de carbono no condensados de dichos anillos monocíclicos y de uno a cinco de los átomos de carbono de dichos anillos bicíclicos que no forman parte del anillo de benceno mostrado en la fórmula (4), por un nitrógeno, oxígeno o azufre y pudiendo estar opcionalmente sustituidos dichos anillos monocíclicos y bicíclicos con uno o más sustituyentes, preferiblemente de cero a dos sustituyentes para los anillos monocíclicos y de cero a tres sustituyentes para los anillos bicíclicos, que se seleccionan, independientemente, entre alquil(C0-6)- ó alcoxi(C1-6)-alquil(C0-6)-, sin que el número total de átomos de carbono exceda de seis y pudiendo estar opcionalmente sustituido cualquiera de los restos alquilo con uno a siete átomos de flúor; oxo, flúor, cloro, (alquil C1-6)2-amino-, -CO2R7, -CONR8R9 y -SO2NR10R11; cada uno de R7, R8, R9, R10 y R11 se selecciona, independientemente, entre hidrógeno y alquilo C1-6, ó R8 y R9, ó R10 y R11, junto con el nitrógeno al que están unidos, forman un anillo de pirrolidina, piperidina, morfolina, azetidina, piperazina, -N-alquil(C1-6)-piperazina o tiomorfolina, o un anillo de tiomorfolina en el que el azufre del anillo se reemplaza por un sulfóxido o sulfona; y cada X es, independientemente, alquileno C1-6.Process for the preparation of any of the intermediate 1,3-substituted indes of formulas (1), (2) and (3) or a mixture thereof, wherein R2 and R3 are independently selected from hydrogen, fluorine , chlorine, -SOq-C1-6 alkyl, where q is zero, one or two, (C1-6 alkyl) 2-amino, -CO2R7, -CONR8R9, -SO2NR10R11, aryl-alkyl (C0-3) - or aryl- (C0-3) alkyl -O-, said aryl being selected from phenyl and naphthyl, heteroaryl (C0-3) alkyl- or heteroaryl-C0-3-alkyl-O-, said heteroaryl being selected from aromatic rings of five to seven members containing one to four heteroatoms selected from oxygen, nitrogen and sulfur; X2-alkyl (C0-6) - and X2-alkoxy (C1-6) -alkyl (C0-6) -, being X2 absent or being X2 alkyl (C1-6) -amino- or (alkyl (C1-6) ) 2-amino and containing the alkyl (C0-6) - or (C1-6) alkoxy (C0-6) - of said X2-alkyl (C0-6) - or X2-alkoxy (C1-6) moieties -alkyl (C0-6) - at least one carbon atom and can optionally be replaced from one to three of the carbon atoms of said alkyl (C0-6) moieties - or (C1-6) alkoxy -alkyl (C0-6 ) - by an oxygen, nitrogen or sulfur atom, with the proviso that any two of said heteroatoms must be separated by at least two carbon atoms and any of the alkyl moieties of said alkyl groups (C0-6) can be - or (C1-6) alkoxy (C0-6) alkyl - optionally substituted with two to seven fluorine atoms and one of the carbon atoms of each of the alkyl moieties of said aryl-alkyl (C0-3) may optionally be replaced ) - and said heteroaryl (C0-3) alkyl - by an oxygen, nitrogen or sulfur atom, and may be option Ally substituted each of the above aryl and heteroaryl groups with one or more substituents, preferably from zero to two substituents, independently selected from C1-6 alkyl optionally substituted with one to seven fluorine atoms, C1-6 alkoxy optionally substituted with two to seven atoms of fluorine, chlorine, fluorine, ((C1-6) alkyl) 2-amino-, -CO2R7, -CONR8R9 and -SO2NR10R11; or R2 and R3, together with the carbons to which they are attached, form a monocyclic carbocyclic ring of four to seven members, or bicyclic of ten to fourteen members, which may be saturated or unsaturated, and may be optionally and independently replaced from one to three of the non-condensed carbon atoms of said monocyclic rings and one to five of the carbon atoms of said bicyclic rings that are not part of the benzene ring shown in the formula (4), by a nitrogen, oxygen or sulfur and being able said monocyclic and bicyclic rings are optionally substituted with one or more substituents, preferably from zero to two substituents for the monocyclic rings and from zero to three substituents for the bicyclic rings, which are independently selected from (C0-6) alkyl- or (C1-6) alkoxy-(C0-6) -alkyl, without the total number of carbon atoms exceeding six and any of the res may be optionally substituted Cough alkyl with one to seven fluorine atoms; oxo, fluorine, chlorine, (C1-6 alkyl) 2-amino-, -CO2R7, -CONR8R9 and -SO2NR10R11; each of R7, R8, R9, R10 and R11 is independently selected from hydrogen and C1-6 alkyl, or R8 and R9, or R10 and R11, together with the nitrogen to which they are attached, form a pyrrolidine ring, piperidine, morpholine, azetidine, piperazine, -N-(C1-6) alkylpiperazine or thiomorpholine, or a thiomorpholine ring in which the ring sulfur is replaced by a sulfoxide or sulfone; and each X is, independently, C1-6 alkylene; R5 is C1-6 alkyl or Si (R12) 3; R1 is an electron extraction group selected from cyano, alkoxycarbonyl, alkylcarbonyl, arylcarbonyl, aryl, nitro, trifluoromethyl and sulfonyl; each R4 is independently H, C1-6 alkyl, H (L) 3N +, or a metal cation, including alkali metal cations of Na, K, Li or Cs; or two R11 groups together form a C2-3 alkylene bond; each L is independently H, C1-6 alkyl, phenyl or benzyl; and each R12 is independently C1-6 alkyl or phenyl. The compounds of formulas (1), (2) and (3), or mixtures thereof, are useful in the preparation of compounds of formula (4) in which R 6 is hydrogen; wherein R2 and R3 are independently selected from hydrogen, fluorine, chlorine, -SOq-C1-6 alkyl, where zero, one or two, (C1-6 alkyl) 2-amino, -CO2R7, -CONR8R9, -SO2NR10R11, aryl-alkyl (C0-3) - or aryl-alkyl (C0-3) -O-, said aryl being selected from phenyl and naphthyl, heteroaryl-alkyl (C0-3) - or heteroaryl-alkyl (C0-3) ) -O-, said heteroaryl being selected from five to seven member aromatic rings containing one to four heteroatoms selected from oxygen, nitrogen and sulfur; X2-alkyl (C0-6) - and X2-alkoxy (C1-6) -alkyl (C0-6) -, being X2 absent or being X2 alkyl (C1-6) -amino- or (alkyl (C1-6) ) 2-amino and containing the alkyl (C0-6) - or (C1-6) alkoxy (C0-6) - of said X2-alkyl (C0-6) - or X2-alkoxy (C1-6) moieties -alkyl (C0-6) - at least one carbon atom and can optionally be replaced from one to three of the carbon atoms of said alkyl (C0-6) moieties - or (C1-6) alkoxy -alkyl (C0-6 ) - by an oxygen, nitrogen or sulfur atom, with the proviso that any two of said heteroatoms must be separated by at least two carbon atoms and any of the alkyl moieties of said alkyl groups (C0-6) can be - or (C1-6) alkoxy (C0-6) alkyl - optionally substituted with two to seven fluorine atoms and one of the carbon atoms of each of the alkyl moieties of said aryl-alkyl (C0-3) may optionally be replaced ) - and said heteroaryl (C0-3) alkyl - by an oxygen, nitrogen or sulfur atom, and may be option Ally substituted each of the above aryl and heteroaryl groups with one or more substituents, preferably from zero to two substituents, independently selected from C1-6 alkyl optionally substituted with one to seven fluorine atoms, C1-6 alkoxy optionally substituted with two to seven atoms of fluorine, chlorine, fluorine, ((C1-6) alkyl) 2-amino-, -CO2R7, -CONR8R9 and -SO2NR10R11; or R2 and R3, together with the carbons to which they are attached, form a monocyclic carbocyclic ring of four to seven members, or bicyclic of ten to fourteen members, which may be saturated or unsaturated, and may be optionally and independently replaced from one to three of the non-condensed carbon atoms of said monocyclic rings and one to five of the carbon atoms of said bicyclic rings that are not part of the benzene ring shown in the formula (4), by a nitrogen, oxygen or sulfur and being able said monocyclic and bicyclic rings are optionally substituted with one or more substituents, preferably from zero to two substituents for the monocyclic rings and from zero to three substituents for the bicyclic rings, which are independently selected from (C0-6) alkyl- or (C1-6) alkoxy-(C0-6) -alkyl, without the total number of carbon atoms exceeding six and any of the res may be optionally substituted Cough alkyl with one to seven fluorine atoms; oxo, fluorine, chlorine, (C1-6 alkyl) 2-amino-, -CO2R7, -CONR8R9 and -SO2NR10R11; each of R7, R8, R9, R10 and R11 is independently selected from hydrogen and C1-6 alkyl, or R8 and R9, or R10 and R11, together with the nitrogen to which they are attached, form a pyrrolidine ring, piperidine, morpholine, azetidine, piperazine, -N-(C1-6) alkylpiperazine or thiomorpholine, or a thiomorpholine ring in which the ring sulfur is replaced by a sulfoxide or sulfone; and each X is independently C1-6 alkylene.

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